Structural and vibrational studies of the potential anticancer agent, 5-difluoromethyl-1,3,4-thiadiazole-2-amino by DFT calculations Elida Romano, María Florencia Ladetto, Silvia Antonia Brandán ⇑ Cátedra de Química General, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Ayacucho 471, 4000 San Miguel de Tucumán, Tucumán, Argentina article info Article history: Received 28 December 2012 Received in revised form 24 January 2013 Accepted 24 January 2013 Available online 24 February 2013 Keywords: 5-Difluoromethyl-1,3,4 thiadiazole-2-amino DFT calculation Vibrational spectra Molecular geometry Force field abstract The structural and vibrational properties of a potential anticancer agent, the 5-difluoromethyl-1,3,4 thia- diazole-2- amino derivative and its tautomeric forms were studied by using the available experimental infrared and 1 H, 13 C and 19 F NMR spectra and theoretical calculations based the density functional theory (DFT). The bonds order, atomic charges, charge-transfers and topological properties were studied by means of the Natural Bond Orbital (NBO) and the Atoms in Molecules theory (AIM) calculations. The har- monic vibrational wavenumbers for the optimized geometries were calculated at B3LYP/6-31G / and B3LYP/6-311++G // levels. For a complete assignment of the compound infrared spectrum, the DFT calcu- lations were combined with Pulay’s scaled quantum mechanical force field (SQMFF) methodology in order to fit the theoretical wavenumbers values to the experimental ones. The results were then used to predict the Raman spectra, for which there are no experimental data. An agreement between theoret- ical and available experimental results was found and a complete assignment of all the observed bands in the vibrational spectra was performed. The theoretical vibrational calculations allowed us to obtain a set of scaled force constants fitting the observed wavenumbers. Additionally, the frontier molecular HOMO and LUMO orbitals for the compound were analyzed and compared with those calculated for the 2- amino-1,3,4 thiadiazole molecule. The calculated 1 H, 13 C and 19 F chemicals shifts are in good agreement with the corresponding experimental NMR spectra of the compound in solution. Ó 2013 Elsevier B.V. All rights reserved. 1. Introduction The 1,3,4-thiadiazole-2-amino derivatives are mainly of great pharmacological and medicinal interest because they exhibit a wide range of anticancer activity [1–6], together with in vivo con- ditions [7–9], and the mechanism of action attributed to each derivative are strongly depending on the type of modification of 1,3,4-thiadiazole ring [10–12]. Normally, the fluoro and chloro groups are commonly used to improve the lipid solubility of these compounds using appropriate organic chemical reactions [13–15]. Structurally, the presence of an amino group in the 1,3,4-thiadia- zole ring is associated with a equilibrium tautomeric between the amine and imine forms [16,17]. For these reasons, the studies of its structural properties are very important to characterize com- pletely a 1,3,4-thiadiazole-2-amino derivative. Rzeski et al. [16] have studied the anticancer, neuroprotective activities and compu- tational studies of 2-(4-fluorophenylamino)-5-(2,4-dihydroxy- phenyl)-1,3,4-thiadiazole compound to determine probability of tautomeric transition and indicate potential sites of interactions of the molecule with the receptor. Recently, a new synthetic meth- od for the selective introduction of fluorinated moiety in the thiadiazole ring was published by Fujiwara et al. [15], whose have synthesized the 5-difluoromethyl-1,3,4-thiadiazole-2-amino derivative, demonstrating that the site-selectivity of difluorome- thylation depends on the combined electronic properties of the reacting p-system and incoming radical species. Besides, those authors have characterized that new 1,3,4-thiadiazole-2- amino derivative by using infrared, 1 H, 13 C and 19 F NMR spectroscopies. In this work, as part of our studies on organ fluo- rine [18–22] and heterocyclic compounds of great chemical and pharmacological interest [23–38] and, with the aim of extending information on the structural and vibrational properties of other 1,3,4-thiadiazole-2-amino derivative, we considered here the study of 5-difluoromethyl-1,3,4-thiadiazole-2-amino. So far, the crystal and molecular structure of this compound was not deter- mined and there is no theoretical study concerning both its geom- etry and assignments of their vibrational spectra. The aim of this work is to study the structures and vibrational properties of the two tautomers of 5-difluoromethyl-1,3,4-thiadiazole-2-amino to evaluate the best theory level in order to reproduce the available experimental infrared and 1 H, 13 C and 19 F NMR spectra and carry out its complete assignments. For this purpose, the optimized geometries of both tautomerics structures and its corresponding frequencies were calculated by using the B3LYP/6-31G / and 2210-271X/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.comptc.2013.01.016 ⇑ Corresponding author. Tel.: +54 381 4247752; fax: +54 381 4248169. E-mail address: sbrandan@fbqf.unt.edu.ar (S.A. Brandán). Computational and Theoretical Chemistry 1011 (2013) 57–64 Contents lists available at SciVerse ScienceDirect Computational and Theoretical Chemistry journal homepage: www.elsevier.com/locate/comptc